Hepatitis B virus (HBV) is the most common cause of chronic viral liver disease worldwide. More than 370 million people are chronically infected with HBV leading to nearly one million deaths annually as a result of cirrhosis, liver failure and hepatocellular carcinoma (HCC). Currently available therapies against chronic HBV are expensive, require long-term administration over many years, and often fail to control viral persistence, replication and the progression of necro-inflammatory liver disease. These patients also have the potential for life-long spread of infection. A prophylactic vaccine would provide the best solution for prevention of hepatitis B virus infection. However, the current vaccines while generally effective are less useful in high-risk populations with renal disease or other immunological abnormalities. In addition, the current alum-based vaccine does not induce the type of cell-mediated immunity necessary to treat patients who cannot clear HBV. Therefore, current immunization strategies for hepatitis B cannot be employed as therapeutic vaccines. NanoBio Corporation (Ann Arbor, MI) and the University of Michigan, Michigan Nanotechnology Institute for Medicine and Biological Sciences are developing a nanoemulsion (NE) based adjuvant to enhance the immunogenicity and intranasal delivery of vaccine antigens. Nanoemulsion adjuvants are oil-in-water emulsions prepared by high speed homogenization using innocuous surfactants and solvents as stabilizers with an average droplet size of 200-600 nm. These adjuvants have been shown in animal models to augment targeting of vaccine antigens to the immune system while safely eliciting potent humoral and Th1-type cellular immune responses without inducing inflammation. In addition, the NE vaccine formulations for needle-free delivery are highly stable at room temperature enabling wide spread storage without refrigeration. The overall goal of the Phase I STTR program is to demonstrate that a nanoemulsion-based HBV vaccine can induce immune responses in the presence of confounding factors such as renal failure. This group is at high risk for complications of HBV infection when compared to normal individuals. Therefore, the studies will evaluate and optimize a novel NE-based intranasal vaccine for maximum HBV-specific CD4+ and CD8+ T-cell and humoral immune responses against hepatitis B surface antigen (HBsAg) in normal mice and in mice with chronic renal failure as a model for immune-impaired humans. A pre-clinical safety and tolerability study will be conducted in rabbits as a requirement for progression to human trials. After successful completion of the phase I program, a phase II STTR application will be prepared culminating in an FDA- approved phase I clinical trial to evaluate safety, dose range, immunogenicity and preliminary efficacy against chronic hepatitis B virus in humans with renal failure. In addition, these studies will provide the foundation for the use of this formulation as a therapeutic vaccine for chronically infected individuals. This new vaccine would have great value as a commercialized product to reduce the risk and associated financial burden of HBV- associated liver diseases and deaths both in the United States and globally. PUBLIC HEALTH RELEVANCE: Hepatitis B virus (HBV) is the most common cause of chronic viral liver disease. The proposed studies will develop a novel nanoemulsion-based intranasal vaccine to prevent viral transmission and development of severe complications such as cirrhosis, liver failure and hepatocellular carcinoma (HCC) in immune compromised and chronically infected patients. Development of a safe, needle-free, easy-to-administer and highly effective nanoemulsion-based vaccine would have great value for use as a therapeutic agent against chronic HBV infection in the United States and globally.